tbuckley/cabot-search huggingface dataset:
P399: UNRAVELING THE TUMOR SUPPRESSIVE ROLE OF STAT3Β IN ACUTE MYELOID LEUKEMIA
Authors: S. Edtmayer, A. Witalisz-Siepracka, B. Zdársky, T. Eder, V. Poli, F. Grebien, D. Stoiber
Journal: HemaSphere (2022)

Background: Signal transducer and activator of transcription 3 (STAT3) is a mediator of cytokine signaling existing in two alternatively spliced isoforms known as the full-length isoform STAT3α (770aa) and the C-terminally truncated isoform STAT3β (722aa). Initially STAT3β was described as the dominant negative form of STAT3α. It gained more attention as it turned out to initiate transcription independent of STAT3α and being capable to rescue embryonic lethality in absence of STAT3α. In acute myeloid leukemia (AML) patients, STAT3 has been reported to be constitutively activated thereby promoting proliferation and blast survival. However, most of those studies did not consider the two distinct isoforms of STAT3. Recently, our group identified STAT3β as a novel tumor suppressor and favorable prognostic marker in AML, however the underlying mechanism in leukemic cells remained elusive. Aims: With this study we aim to provide in-depth knowledge on the role of STAT3 isoforms in AML development and disease outcome. Methods: By using murine AML cell lines lacking either STAT3α or STAT3β, we aim to elucidate the STAT3 isoform-specific impact on cellular processes shaping AML development and progression. To gain better understanding we use AML in vivo models and in vitro assays in combination with next-generation sequencing (NGS) approaches to identify molecular mechanisms explaining the tumor suppressive function of STAT3β in AML. In brief, fetal liver-derived stem cells, isolated from STAT3α and STAT3β deficient mice on C57BL/6J background, were transduced with a retrovirus introducing the human fusion-oncogene MLL-AF9, and intravenously transplanted into immunocompromised mice. Results: Animals transplanted with leukemic cells lacking STAT3β showed accelerated disease progression and poorer overall survival confirming its tumor suppressive properties. Furthermore, absence of STAT3β favored leukemic infiltration and migration. Additionally, RNA sequencing revealed that lack of STAT3β in leukemic cells leads to a dysregulation of crucial genes driving leukemogenesis. Summary/Conclusion: Understanding the mechanisms behind the tumor suppressive property of STAT3β has potential translational impact and is crucial to identify novel therapies and preventative strategies. Further validation and ChIP sequencing will provide novel direct target genes of STAT3β which could serve as prognostic or therapeutic molecules.
PB1945: CLINICAL AND MOLECULAR CHARACTERISTICS OF CHILDREN WITH DIAMOND-BLACKFAN ANEMIA (DBA): A SINGLE CENTER EXPERIENCE IN ARGENTINA
Authors: M. F. Mininni, A. Albero, V. J. Avalos, C. Cervio, A. C. Candás, L. Diaz, D. A. Chaves, B. Milanesio, C. M. Pepe, G. Sciuccati
Journal: HemaSphere (2022)

Background: DBA is an inherited bone marrow failure characterized by erythroblastopenia due to an intrinsic defect in erythropoietic progenitors. Half the patients (pts) present with physical malformations. To date 20 ribosomal proteins (RP) genes associated with DBA and 4 non-RP genes related to non-classical DBA (GATA1, TSR2, EPO, ADA2) have been described. Aims: To describe clinical and molecular characteristics and outcomes of a pediatric cohort with DBA admitted at a single tertiary pediatric center in Argentina Methods: Patients diagnosed with DBA between 2004 and 2020 were retrospectively analyzed. DBA diagnosis was based on constitutional normocytic/macrocytic anemia, reticulocytopenia, paucity of bone marrow erythroid precursors and congenital anomalies. Demographic, clinical, and laboratory data, genetic evaluation and outcomes were recorded. Pts were screened for DNA changes by using a custom designed NGS panel with 19 genes related to DBA (RPS19, RPL11, RPL15, RPL18, RPL27, RPL31, RPL35, RPL35A, RPL5, RPS10, RPS15A, RPS24, RPS26, RPS27, RPS28, RPS29, RPS7, TSR2 and GATA1). All identified variants were classified according to the American College of Medical Genetics guidelines. Results: Fifteen unrelated pts with DBA were analyzed, 10 (66%) males, median age at diagnosis 3,7months (25days-6yrs). Twelve pts (80%) had physical malformations. All pts showed paucity of bone marrow erythroid precursors, and only two presented with compromise of other linages. Thirteen pts (87%) received treatment with prednisone, 8 (62%) achieved transfusion independence and half of them achieved complete treatment independency, while five pts (33%) did not respond to steroids and are under transfusion regimen. These 5pts developed liver iron overload and are under chelation therapy. No therapy was required in two pts with variants in GATA1 and RPL5. Median follow-up was 7.1years (1.7-16.7 years), no pts received HSCT and no pts died. Molecular variants were detected in 10/15 pts (66%), 8/10 were novel. Eight variants were classified as ¨pathogenic¨ or ¨likely pathogenic” and two as “of uncertain significance”. Three pts (30%) presented variants in RPS19, two (20%) in RPS26, four (40%) in other RP genes and one pt with non-classical DBA, presented a variant in GATA1. Phenotype and molecular results of the pts are summarized in Table1. Image:Summary/Conclusion: In this cohort of pts with DBA, molecular diagnosis was achieved in the majority. RPS19 variants were the most common. Interestingly, all pts with RPS19 variants presented with malformations, one of them had also pancytopenia at onset. As the penetrance of DBA is incomplete, the molecular diagnosis is important for detecting silent phenotype carriers in the family that will allow for an accurate selection of stem cell donors, genetic counseling and tailored treatment.
P1635: REAL-WORLD DATA OF THROMBOPOIETIN RECEPTOR AGONISTS (TPO-RA) USE IN IMMUNE THROMBOCYTOPENIA (ITP)
Authors: S. Dangudubiyyam, T. Seth, R. Dhawan, M. Aggarwal, P. Kumar, J. Dass, G. Viswanathan, S. Tyagi, M. Mahapatra
Journal: HemaSphere (2022)

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased platelet destruction and impaired platelet production. Over the past decade, use of thrombopoietin receptor agonists (TPO-RA) is steadily rising in ITP. Aims: In this study, we explore the clinical profile of ITP patients on TPO-RA therapy, response rates to TPO-RA therapy, and analyze various factors that can predict outcomes in one of the largest public-sector teaching hospitals in India. Methods: This retrospective observational study included consecutive patients diagnosed with ITP and initiated on TPO-RA therapy (Romiplostim and Eltrombopag) in our clinic from January 1, 2016, to December 31, 2021. Response was defined according to standard international criteria. Results: Over the past six years, 166 patients were initiated on TPO-RA therapy and had a total of 183 treatments (92 eltrombopag, 74 romiplostim, and 17 trailed on both). The median age in our cohort was 28.5 years (range, 1.5-70 years). Pediatric cohort (age < 18 years) included 57 patients. Almost half (N=93; 56%) of the patients had chronic ITP prior to TPO-RA initiation. Baseline characteristics were shown in Table 1. Response rates were significantly higher in the romiplostim group when compared to the eltrombopag group (91% vs. 60%; p<0.001) in the pediatric cohort, which was not observed in the adult cohort (77% vs. 84%; p=0.28). Response rates were significantly higher in the pediatric cohort when compared to the adult cohort in the romiplostim group (91% vs. 77%; p = 0.008); however, adults responded better in the eltrombopag group (84% vs. 60%; p<0.001). There was a significant reduction in bleeding manifestations at 1 month when compared with baseline (20% vs. 61%; p<0.001). On univariate analysis, prior splenectomy was a predictor of poor response to TPO-RA therapy. However, on multivariate analysis, age, sex, ITP duration, prior splenectomy, prior lines of therapy were not predictive of response. Adverse events: Thrombocytosis was noted in 12 (7%) patients with no evidence of thrombosis, and 2 (1%) patients progressed to myelodysplastic syndrome. Of the 17 patients who were trailed on both therapies, 6 (3.5%) patients failed both TPO-RA therapies. Among the 54 (31%) patients who discontinued therapy, 11 (6.6%) patients achieved durable response off treatment. The median follow-up duration was 13 months (range, 0.8-79 months). Image:Summary/Conclusion: Response rates to TPO-RA therapy in our cohort are consistent with those reported from the West. We observed that response rates were significantly higher in our pediatric cohort when compared to our adult cohort.
PB2277: ANALYSIS ON POLLUTION STATUS AND INFLUENCING FACTORS OF NURSES’ UNIFORMS IN HEMATOLOGY GENERAL WARD
Authors: X. Du, L. Wang, W. He, Q. Li, L. Tang, X. Feng, P. Zhou, N. Zhao, X. Zhang, C. Song
Journal: HemaSphere (2022)

Background: In clinical work, nurses are the direct caregivers of patients, and they need to cooperate with doctors to observe patients’ conditions and carry out a number of clinical operations. Therefore, the contamination of nurses’ uniforms should be taken into account by hospital infection control workers. Contaminated nurses’ uniforms will reduce the quality of nursing and affect the treatment and rehabilitation of diseases, especially the hematological tumors patients who with low immunity. According to the study, nurses should change cleaning. Aims: Investigate and analyze the contamination of nurses’ uniforms after different working hours in hematology general ward, in order to providing some references to improve the quality of hospital infection management. Methods: From July to November 2021, front-line clinical nurses in the hematology general ward of a tertiary hospital in Chongqing were selected as the research objects by convenience sampling method. Samples were taken from different parts of the nurse at 8 different times, which including when changing clean uniform, and 1h, 3h, 6h, 2d, 3d, 4d and 5d after changing clean uniforms. Results: In this study, a total of 264 qualified specimens were collected from 33 nurses’ uniforms. Descriptive analysis showed that the bacterial colony counts of cuff, abdomen and front chest at the 6th hour after changing clean uniforms were (11.30±3.56) CFU/cm2, (8.79±2.33) CFU/cm2, and (11.06±2.71)CFU/cm2 and the qualified rates of cleanliness were 0, 9.1% and 3.0% respectively. Multiple linear regression analysis showed that, at the 6th hour after changing clean uniforms, the main influence factors of the bacterial colony count on the cuffs were work times, environmental humidity and the height of nurse, the fore chests were work times and the height of nurse, and the abdomens were work times, the total number of patients and the number of first-grade patients (all P<0.05). After 5 days, the main influence factors of the bacterial colony count on the cuffs were work times and the total number of patients, the fore chests were work times and the height of nurse, and the abdomens were work times and the total number of patients (all P<0.05). Summary/Conclusion: It is necessary for nurses in general hematology department to increase the frequency of changing nurses’ uniforms and improve the cleanliness to ensure the nursing quality and patient safety. For nursing managers, it is essential to optimize the allocation of human resources further and provide necessary infection protection equipment to reduce the risk of hospital-acquired infection caused by the serious pollution of nurses’ work clothes.
P1116: SAFETY, PHARMACOKINETIC (PK), PHARMACODYNAMIC (PD) AND ACTIVITY OF THE HIGHLY SELECTIVE PHOSPHOINOSITIDE 3-KINASE INHIBITOR DELTA (PI3KΔ) INHIBITOR IOA-244 IN PATIENTS WITH FOLLICULAR LYMPHOMA (FL)
Authors: C. Carlostella, M. Lahn, T. Hammett, L. van der Veen, Z. Johnson, C. Pickering, A. Santoro
Journal: HemaSphere (2022)

Background: IOA-244 is a highly selective inhibitor of PI3Kδ, and has a favourable safety and ADME profile in patients (pts) with solid malignancies. In pts with uveal melanoma, IOA-244 also reduced circulating Tregs counts at the biologically effective dose (BED) range. Aims: As part of the First-in-human (FiH) dose escalation study, pts with FL received IOA-244 at the BED range established in patients with solid malignancies to confirm its favourable safety and PK profile in pts with haematologic malignancies. Methods: IOA-244 was investigated in a two-part FIH study. Part A explored the continuous daily dosing of IOA-244 at 10, 20, 40 and 80 mg in pts with solid malignancies and at 20 mg and 80 mg in pts with FL. Part B consists of expansion cohorts of specific tumour indications, including pts with lymphoma. Primary objective: safety of the anticipated BED, or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); Lugano-based responses; PFS and OS Results: While Part A for solid malignancies have previously been reported (Di Giacomo et al 2021), we here report for the first time the safety, PK, PD and activity of pts with FL. This part of the study is still ongoing in patients with FL and is anticipated to be completed in 2022. Pts at the first cohort of 20 mg QD daily (4/4; 2 female and 2 males) had no DLT and no dose interruptions. Transient platelet reduction (G3) and AST/ALT elevation (G2) were observed in 1/4 pts, which improved while pt was on therapy. The PK and ADME profile was consistent with the ones observed in pts with solid malignancies. One patient had FL and DLBCL as prior co-primary malignancy with 7 prior lines of therapy. The other 3 pts had 1-3 prior lines of therapy. The best response was SD (1/3 pts) and all pts progressed after completing 2 cycles. LDH was initially elevated in 2/4 pts which subsequently decreased on therapy. 3/4 pts had low Treg counts at baseline. Additional pts are being recruited at the RP2D for solid malignancies, at 80 mg QD. Reference: Di Giacomo et al. Annals of Oncology (2021) 32 (suppl_7): S1428-S1457. 10.1016/annonc/annonc787 Summary/Conclusion: The PK and ADME profile of IOA-244 in pts with FL appears to match that in pts with solid malignancies. Additional pts at the 80 mg QD dose are expected to match the safety observed in pts with solid malignancies. In contrast to other PI3Kd inhibitors, IOA-244 is highly selective and may therefore target Tregs in pts with FL without off-target effects induced by inhibition of other PI3K isoenzymes.
Immunomodulation therapy offers new molecular strategies to treat UTI
Authors: Daniel Butler, Ines Ambite, Murphy Lam Yim Wan, Thi Hien Tran, Björn Wullt, Catharina Svanborg
Journal: Nature Reviews Urology (2022)

Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1β, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise. Hyperactivation of innate immunity is a disease determinant in urinary tract infections (UTIs). Modulation of innate immunity has promise as a therapy for UTIs. In this Review, the authors discuss potential mechanisms and immunomodulatory therapeutic strategies in UTIs.
PB2188: APPLICATION PROSPECT OF LOW DOSE PORCINE ANTITHYMOCYTE GLOBULIN IN HLA MATCHED SIBLING DONOR TRANSPLANTATION
Authors: X. chen, R. zhang, W. zhai, Q. ma, A. pang, D. yang, Y. he, J. wei, S. feng, M. han, E. Jiang
Journal: HemaSphere (2022)

Background: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Aims: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Methods: The clinical data of 60 patients with hematological malignancies who received MSD-HSCT from July 2020 to October 2021 were analyzed retrospectively. These patients / donors were older than 40 years old or the donors were female. Of these, 30 patients received Low-dose porcine ATG as a part of conditioning regimen (P-ATG group), while the other 30 patients didn’t receive ATG (No-ATG group). In addition to the fact that the ages of the patients and donor were older in P-ATG group, all patients’ other baseline characteristics and donor condition of the two groups were similar. Results: All patients engrafted in two groups. There were significant differences in the incidence of aGVHD ([23.3 (10.1-39.7)%] vs [50.0 (30.8-66.5)%], P = 0.0276), grade III-IV aGVHD ([16.7 (5.94-32.1)%] vs [40.0 (22.4-57.0)%], P = 0.0491) and cGVHD ([22.4 (6.03-45.1)%] vs [69.0 (43.4-84.8)%], P = 0.0009) between the P-ATG and No-ATG groups. But there was no significant difference in terms of 1-year OS ([79.9 (60.5-90.4)%] vs [84.0 (61.2-94.0)%], P = 0.4411) or RR ([13.6 (2.73-33.2)%] vs [15.2 (4.40-32.1)%], P = 0.7416). And there was also no significant difference with regard to the incidence of severe bacterial infection (P = 0.612), invasive fungal disease (P = 1.000) or CMV infection (P = 0.2976). 80% (4 / 5) of patients in P-ATG group died of secondary infection after grade III-IV aGVHD, and 16.7% (2 / 12) in No-ATG group. Summary/Conclusion: The application of low-dose P-ATG in the conditioning regimen of MSD-HSCT can significantly reduce the incidence of aGVHD, grade III-IV aGVHD and cGVHD, doesn’t increase the risk of recurrence after transplantation in patients / donors older than 40 years old or female donors. However, the patients in P-ATG group were older and had high mortality caused by secondary infection after grade III-IV aGVHD. Therefore, there was no significant difference in OS between the two groups.
P1610: IMPACT OF COVID-19 ON PATIENTS TREATED WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION - A RETROSPECTIVE COHORT STUDY
Authors: T. Silfverberg, H. Cherif, K. Carlson, B. Wahlin
Journal: HemaSphere (2022)

Background: Early studies of COVID-19 reported high mortality rates in patients with malignancy and who were immunocompromised. The immunosuppression related to autologous hematopoietic stem cell transplantation (ASCT) together with the risk of contracting severe SARS-CoV-2 lead to modifications in the therapy recommendations and, in many cases, to postponed treatment. Aims: To describe how Coronavirus Disease 2019 (COVID-19) affect patients with hematological malignancies treated with ASCT. Methods: This retrospective observational cohort study includes all patients with hematological malignancies treated with ASCT in Sweden from 1 January 2020 until 31 December 2020. Patients who subsequently tested positive for SARS-CoV-2 until 31 March 2021 were analyzed for morbidity, mortality, need for supportive care and risk factors involved in COVID-19. Results: The study identified 442 patients who underwent ASCT in Sweden in 2020, among whom 20 (4.5%) subsequently contracted COVID-19. The overall mortality was 15% and the COVID-19 related mortality 10%. The absolute risk of COVID-19 related mortality was 0.45% among patients treated with ASCT. Six (35%) patients were hospitalized, among which four (24%) needed supplementary oxygen and two (12%) intensive care. Image:Summary/Conclusion: ASCT patients have a higher risk of severe outcome of COVID-19 compared to the general population. The risk of death, need for hospital care, oxygen and intensive care was lower in this study compared with most previous studies, possibly because of less missing asymptomatic patients. The risk of contracting SARS-CoV-2 was comparable with the general population. This study support performing ASCT for treatment of hematological malignancies despite the COVID-19 pandemic.
P1557: DISTINGUISHING OF IRON REFRACTORY IRON DEFICIENCY ANEMIA FROM IRON DEFICIENCY ANEMIA AND THALASSEMIA TRAIT BY SYSMEX RESEARCH RED CELL PARAMETERS
Authors: E. Yilmaz, Z. Kaya, S. Kirkiz, Ü. Koçak
Journal: HemaSphere (2022)

Background: Iron refractory iron deficiency anemia (IRIDA), iron deficiency anemia (IDA), and Thalassemia trait (TT) are the most common causes of microcytic anemia. It is possible to discriminate between IDA and TT by routine complete blood count (CBC), hemoglobin (Hb) electrophoresis and iron parameters; however, it is very difficult to distinguish IRIDA from IDA and TT using only routine CBC and iron parameters. Aims: The aim was to distinguish IRIDA from IDA and TT using Sysmex research red cell parameters. Methods: The study included a total of 25 patients (n=10, TT; n=10, true IDA; n= 5, genetically confirmed IRIDA). Traditional [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell count (RBC), and red cell distribution volume (%RDW)] and new red cell parameters [percentage hypochromic RBCs (%Hypo-He); percentage microcytic RBCs (%Micro-R)] were measured in a Sysmex-XN®2000 (Sysmex Corporation, Kobe, Japan), along with iron parameters. Participants' disorders were categorized based on patients' ferritin, Hb electrophoresis, genetic results, and CBC values. Results: Compared with the IDA patients, IRIDA patients had significantly higher mean levels of ferritin, RBC, %Hypo-He, %Micro-R and significantly lower mean levels of serum iron level MCV, MCH, and MCHC values (p<0.05 for all). Compared with TT patients, IRIDA patients had significantly higher mean levels of ferritin, %Hypo-He and %RD,W and significantly lower mean levels of serum iron level and MCH values (p<0.05 for all). The RBC, Micro-R, Hypo-He, MCV and MCH cut-off values for discriminating IRIDA from IDA patients were 4.9µL, %60, 50%, 60fL, and 16.0pg, respectively. The RDW, Hypo-He, and MCH cut-off values for discriminating IRIDA from TT patients were %19, %30, and 17.0pg, respectively. Summary/Conclusion: This first study has examined the utility of new red cell parameters in patients with IRIDA. Our findings should be confirmed in larger studies; however, we believe that higher percentage of hypochromic microcytic erythrocytes with an elevated RBC value may be useful predictors for distinguishing IRIDA from IDA patients. As well, a moderate percentage of hypochromic erythrocytes with high RDW value can guide physicians in discriminating IRIDA from TT patients